Synthesis Of (Z)-3,5-dihydroxy-4- Isopropylstilbene

For the stilbene compounds,there are E-isomers and Z-isomers.E-isomers generally show the significant physiological activities but the opposite Z-isomers display nothing.While Z-isomer is an inevitable by-product in the preparation for E-isomer,it is very important to find a reasonable synthetic method for Z-isomers.(E)-3,5-dihydroxy-4-isopropylstilbene(Benvitimod),which is a new medicine for treatment of psoriasis and eczema,belongs to the hydroxystilbene family.Because of symbiotic and configuration transforming with E-isomer,(Z)-3,5-dihydroxy-4-isopropylstilbene always exists as a main and inevitable impurity in the preparation of Benvitimod.Research on the synthesis of(Z)-3,5-dihydroxy-4-isopropylstilbene is important on assuring the effectiveness and reducing adverse effect of Benvitimod.In this paper,we provided a total synthetic method for Benvitimod impurity(Z)-3,5-dihydroxy-4-isopropylstilbene starting from 3,5-dihydroxybenzoic acid,through isopropyl reaction,esterification and etherification,reduction,oxidation,Perkin condensation,decarboxylation and demethylation.The optimal reaction condition was also determined in detail.In addition,another method to synthesize(Z)-3,5-dihydroxy-4-isopropylstilbene by is also introduced.There occurs the inversion of configuration that Benvitimod transforms into Z-isomer under UV irradiation.Moreover,a novel stabilityindicating HPLC method is presented for the determination of(Z)-3,5-dihydroxy-4-isopropylstilbene,and the method validation is also conducted.